Effects of toceranib compared with sorafenib on monocrotaline-induced pulmonary arterial hypertension and cardiopulmonary remodeling in rats

Abstract

Sorafenib reverses pulmonary arterial hypertension (PAH) and cardiopulmonary remodeling (CPR), but the effects of toceranib are unknown. This study investigated anti-remodeling effects and determined optimal doses of toceranib and sorafenib on monocrotaline (MCT)-induced PAH and CPR in rats. MCT-treated rats were orally treated with a 14-day course of sorafenib (10, 30, or 100 mg/kg), toceranib (1, 3, or 10 mg/kg), or water. Both sorafenib and toceranib significantly reversed the right ventricular (RV) hypertrophy at 10 mg/kg, but only sorafenib significantly improved the RV systolic and mean pressures. Sorafenib significantly normalized the B-type natriuretic peptide mRNA level of the RV and increased the non-muscularized pulmonary artery percentage. However, these effects were only observed at the highest toceranib dose, and neither toceranib dose reduced the fully muscularized pulmonary artery percentage. Further, the inhibition on vascular endothelial growth factor (VEGF) signaling was stronger in sorafenib than in toceranib. Besides the stronger inhibition on mitogen-activated protein kinase signaling, the greater reversal ability of sorafenib may be also due to the simultaneous blockade on the C-X-C chemokine receptor type 4 and autophagy induction. Toceranib insignificantly reversed CPR, and a high-dose therapy did not improve the RV hemodynamic outcomes. Sorafenib significantly reversed CPR, and a low-dose sorafenib therapy may be a suitable therapeutic agent for PAH.